The overall goal of the proposed research is to characterize the pharmacological basis of the subjective effects of alcohol in a non-human primate model. This model uses a drug discrimination procedures to define receptor mechanisms that mediate the interoceptive (or subjective) stimulus effects of ethanol. Studies in the preceding period of funding have suggested that positive modulation of GABAA receptors appears to produce the most robust ethanol-like stimulus across training dose and gender. Of the GABAA ligands, the endogenous neurosteroids offer a unique opportunity to study mechanisms of physiological states that alter sensitivity to the subjective effects of ethanol. The proposed studies will use neurosteroids to define GABAA, subtypes of receptors that mediate the discriminative stimulus effects of ethanol; test novel steroid analogs to produce discriminative stimulus effects though NMDA inhibition; and use menstrual cycle phase to test hypotheses concerning alterations in GABAA receptor subtypes leading to changes in sensitivity to ethanol. Perhaps functionally linked to the GABAA receptor system are specific serotonin receptor subtypes that produce opposite effects on sensitivity to ethanol's discriminative stimulus effects. The proposed studies will further characterize these interactions. Overall, the results from the proposed studies should advance our understanding of endogenous mechanisms that alter sensitivity to the subjective effects of ethanol in a non-human primate species.
The specific aims are the research are: 1) To characterize the neurosteroid modulation of GABAA receptors and the discriminative stimulus effects of ethanol. 2) To characterize the neurosteroid modulation of NMDA receptors and the discriminative stimulus effects of ethanol. 3) To characterize the influence of menstrual cycle phase on neurosteroid modulation of the discriminative stimulus effects of ethanol. 4) To characterize the 5-HT1D and 5-HT2C modulation of the discriminative stimulus effects of ethanol.
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